Original Article
Ondansetron plus Metopimazine Compared with Ondansetron Alone in Patients Receiving Moderately Emetogenic Chemotherapy
N Engl J Med 1993; 328:1076-1080April 15, 1993
- Abstract
Background and Methods
The serotonin (5-hydroxytryptamine3) antagonists have improved the treatment of acute chemotherapy-induced nausea and vomiting, but their ability to prevent delayed nausea and vomiting seems less pronounced. The results of a preliminary open trial suggested that the addition of a selective dopamine D2 antagonist could improve the antiemetic efficacy of the serotonin antagonists. In a randomized, double-blind, crossover trial, we compared oral treatment with ondansetron (8 mg twice a day) and the dopamine D2 antagonist metopimazine (30 mg four times a day) with treatment with ondansetron alone for three days in 30 patients who had vomited during the previous cycle of chemotherapy. All the patients received moderately emetogenic chemotherapy.
Results
Combination treatment with ondansetron and metopimazine significantly reduced the incidence of acute (P = 0.006) and delayed (P = 0.02) nausea and acute (P = 0.02) and delayed (P = 0.006) vomiting, as compared with treatment with ondansetron alone. Patients had significantly fewer days of nausea (P = 0.03) and vomiting (P = 0.003) if they received combination therapy. Sixty-seven percent of the patients preferred ondansetron and metopimazine, and 33 percent favored ondansetron alone (P = 0.10). Adverse reactions were mild with both regimens. With the exception of constipation, which was reported more frequently with combination therapy (P = 0.03), there were no significant differences in adverse reactions.
Conclusions
Ondansetron plus metopimazine is a highly effective and safe antiemetic regimen that is markedly superior to treatment with ondansetron alone in patients receiving moderately emetogenic chemotherapy.
Media in This Article
Table 1
Characteristics of the 30 Patients.Table 2
Number of Emetic Episodes in 30 Patients Receiving Ondansetron Alone or Ondansetron and Metopimazine.Article Activity
- Article
Chemotherapy-induced emesis is thought to be mediated by receptors located in the chemoreceptor trigger zone of the area postrema and in the gastrointestinal tract. Until recently, dopamine D2 receptors were considered the most important, but the identification of serotonin (5-hydroxytryptamine3) receptors in these two areas1,2 and the finding that the dopamine D2 antagonist metoclopramide, when given in high doses, is also a serotonin antagonist1 and probably owes its antiemetic effect to the blockade of this receptor, have necessitated a reexamination of the mechanism. Today, more selective and potent serotonin antagonists have been developed, and the contribution of these agents to the reduction of chemotherapy-induced nausea and vomiting is substantial. The efficacy and selectivity of these drugs have even called into question the importance of the conventional antiemetics, the dopamine D2 antagonists3.
The serotonin antagonist ondansetron is effective against acute emesis and is superior to metoclopramide4-9. In patients receiving cisplatin, the effect is enhanced by the addition of dexamethasone10-12. The effect of ondansetron and other serotonin antagonists on delayed nausea and vomiting, however, seems to be less pronounced5-9,13-15. Serotonin receptors have a major role in acute emesis, but probably are of only minor importance in delayed emesis. In patients receiving moderately emetogenic chemotherapy, ondansetron has generally been given in a dosage of 8 mg three times a day,7-9 but in a recent double-blind trial involving 324 patients, a twice-daily dose of 8 mg was just as effective16.
The dopamine D2 antagonist metopimazine, a piperidine derivative of phenothiazine, is closely related to chlorpromazine, but is more potent and less toxic17. In prospective, randomized studies, metopimazine was superior to placebo18,19 and equal to prochlorperazine18 in the treatment of chemotherapy-induced nausea and vomiting and as effective as chlorpromazine against radiation-induced emesis17. Higher doses of metopimazine seem to enhance the antiemetic effect,19-21 with orthostatic hypotension being the dose-limiting adverse reaction21 when oral metopimazine is given repeatedly in doses of more than 30 mg22. Though a selective dopamine D2 antagonist, metopimazine has no extrapyramidal side effects,21,22 a frequent problem during treatment with metoclopramide23.
The vast majority of antiemetic trials enroll patients receiving chemotherapy for the first time. These trials do not always reflect the clinical situation, since patients who have previously received chemotherapy are more likely to have nausea and vomiting. Consequently, we compared the antiemetic efficacy and safety of ondansetron alone with those of ondansetron in combination with metopimazine in patients who had received chemotherapy before and who had had at least one vomiting episode. The severity and duration of acute and delayed nausea and vomiting were evaluated.
Methods
Patients
A randomized, double-blind, placebo-controlled, crossover design was used to evaluate 30 patients who received outpatient adjuvant chemotherapy for breast cancer in stage I or II. No patient had any other severe concurrent illness, metastases to the central nervous system, or other known causes of vomiting. None had received antiemetics within 24 hours (or glucocorticoids during the week) before the study began. None had previously received ondansetron or metopimazine, but during previous cycles of chemotherapy all had been treated with metoclopramide alone or in combination with prednisolone or lorazepam. Patients were asked about the number of vomiting episodes during their last cycle of chemotherapy (three weeks before the study), and those who had had at least one vomiting episode and who had no anticipatory nausea or vomiting (defined as any nausea or vomiting during the 24 hours before chemotherapy began) at enrollment were included in the study. The characteristics of the patients are given in Table 1Table 1
Characteristics of the 30 Patients..Chemotherapy and Antiemetic Treatment
The following chemotherapy regimens were used: cyclophosphamide at a dose of 600 mg per square meter of body-surface area, methotrexate at a dose of 40 mg per square meter, and fluorouracil at a dose of 600 mg per square meter; cyclophosphamide at a dose of 600 mg per square meter, epirubicin at a dose of 60 mg per square meter, and fluorouracil at a dose of 600 mg per square meter; and cyclophosphamide alone at a dose of 850 mg per square meter. All drugs were given intravenously every three weeks.
The patients were randomly assigned to oral treatment with either 8 mg of ondansetron twice a day and 30 mg of metopimazine four times a day or 8 mg of ondansetron twice a day and placebo four times a day for three days. On day 1 patients received one tablet of ondansetron and one tablet of metopimazine (or an identical-appearing placebo tablet) before chemotherapy began. The second dose of metopimazine (or placebo) was given before dinner, and the third dose of metopimazine (or placebo) was given together with the second dose of ondansetron just before the patient went to bed. On days 2 and 3, metopimazine (or placebo) was given 30 minutes before breakfast, lunch, and dinner and 30 minutes before the patient went to bed. Ondansetron was given together with the first and third doses of metopimazine (or placebo). This schedule ensured optimal absorption of the drugs, since concomitant food intake reduces the absorption of metopimazine24. The study medication was given in a plastic container with a separate compartment for each dose. To ensure that they took the study medication, the patients recorded the number of tablets taken each day. The patients returned the container at the next chemotherapy session, and the number of unused study tablets was counted. Three weeks later, when the patients returned for their next course of chemotherapy, they were crossed over to the alternative antiemetic treatment.
Assessment of Antiemetic Effectiveness
On days 1 through 5 after chemotherapy all patients recorded on diary cards the number of vomiting episodes and dry retches and the severity of nausea and other adverse events during each 24-hour period. Any vomit productive of liquid or any dry retch was considered a single emetic episode. The patients assessed the severity of nausea with a graded scale consisting of the following descriptors: “none,” “mild, did not interfere with daily life,” “moderate, interfered with daily life,” and “severe, bedridden due to nausea.” This scale is the same as that recommended by Olver et al.25 and has been found to be equivalent to a visual-analogue scale26. The patients also assessed other adverse events with a graded scale. On the first, second, and third days after chemotherapy was administered, the patients recorded the number of study tablets taken. On days 2 and 5, a research nurse telephoned all the patients (the same research nurse called during both courses of treatment) to ensure that they completed the diary cards. To assess the frequency of anticipatory nausea and vomiting, the same research nurse telephoned the patients three days before the next cycle of chemotherapy and reminded them that they should again record the number of vomiting episodes and dry retches, and grade any nausea. These data were recorded for the three days before each course of chemotherapy. After completing both courses (i.e., on day 5 after the crossover), the patients were asked about their treatment preference, if any.
Ethical Considerations
Written informed consent was obtained from all patients. The study complied with the Helsinki II Declaration and was approved by the Scientific Ethics Committee of Copenhagen County and by the Danish medical health authorities.
Statistical Analysis
The Mann-Whitney U test and the t-test for unpaired differences were used to determine the presence or absence of a period effect and carryover effect27. Both tests were applied to all variables investigated (the frequency of emetic episodes and the severity of nausea on day 1 [acute episodes], days 2 through 5 [delayed episodes], and days 1 through 5 [overall episodes]; the number of days on which emetic episodes occurred; the number on which nausea occurred; and treatment preference). A P value below 0.10 was considered to indicate the presence of a period or carryover effect, and such a finding implied that only data from the first course could be used. The Wilcoxon matched-pairs test was used to assess differences in the efficacy and tolerability of treatment28. The sign test was used to assess differences in treatment preference. All tests were two-tailed. A P value below 0.05 was considered to indicate statistical significance. Analyses of nausea and vomiting were done separately for day 1 (acute episodes), days 2 through 5 (delayed episodes), and days 1 through 5 (overall episodes). The analyses of days 2 through 5 and days 1 through 5 were based on the number of emetic episodes and the severity of nausea recorded on the worst day during a particular period and, for emesis, on the total number of emetic episodes recorded during the period.
Results
All 30 patients completed the crossover study. None of the variables investigated showed an effect of carryover or period, since the P values ranged from 0.33 to 0.98 (by the Mann-Whitney U test) and from 0.19 to 1.00 (by the t-test for unpaired differences). All crossover data were therefore included in the analyses.
Twenty-six patients (87 percent) took all the study tablets as scheduled. Three patients missed one or more doses on days 2 and 3 during both courses (one because she forgot to take the tablets, and two because of treatment failure). One patient forgot a single dose (of ondansetron) during the second course. None of the 30 patients received any additional antiemetics.
Twenty-eight patients received the same type of chemotherapy in both courses. Two patients received only half the prescribed dose of chemotherapy in one of the courses. Both of these patients had fewer emetic episodes and less nausea with combination therapy and expressed a preference for therapy with ondansetron plus metopimazine; the first was given combination therapy after having received 100 percent of the dose of chemotherapy and the second after having received 50 percent of the dose. Exclusion of the data on the second of these patients did not influence any of the variables investigated. Therefore, data on all 30 patients were included in the analysis on the basis of the intention to treat.
Acute and Delayed Emesis
The number of emetic episodes (vomiting episodes and retches) on day 1, days 2 through 5, and days 1 through 5 is shown in Table 2Table 2
Number of Emetic Episodes in 30 Patients Receiving Ondansetron Alone or Ondansetron and Metopimazine.. The addition of metopimazine to the ondansetron regimen significantly reduced the number of acute episodes (day 1), delayed episodes (days 2 through 5), and overall episodes (days 1 through 5). Combination therapy was especially effective in controlling delayed emesis, since none of the patients so treated had more than two emetic episodes a day during days 2 through 5; in contrast, seven patients (23 percent) given ondansetron alone had three or more episodes (Table 2).Acute and Delayed Nausea
The severity of nausea is shown in Table 3Table 3
Severity of Nausea in 30 Patients Receiving Ondansetron Alone or Ondansetron and Metopimazine.. The combination therapy was significantly superior to ondansetron alone on day 1, days 2 through 5, and days 1 through 5. None of the patients had severe acute or delayed nausea during treatment with ondansetron and metopimazine, as compared with seven patients (23 percent) who had severe nausea on one or more days during treatment with ondansetron (Table 3).Duration of Nausea and Vomiting
The median number of days on which emetic episodes occurred was zero (range, zero to four) with the combination therapy, as compared with one (range, zero to four) with ondansetron therapy alone (P = 0.003). Nausea occurred on a median of two days (range, zero to five) and three days (range, zero to five), respectively (P = 0.03).
Treatment Preference
All patients expressed a treatment preference. Twenty patients (67 percent) preferred the combination therapy, and 10 (33 percent) preferred ondansetron alone (P = 0.10). The preferences expressed by the patients were independent of the sequence of antiemetic treatment; among the 20 patients who preferred treatment with ondansetron and metopimazine, 10 received this combination during the first course and 10 received ondansetron alone during the first course.
Anticipatory Nausea and Vomiting
None of the patients had anticipatory nausea or vomiting before they entered the study, and only two patients had anticipatory nausea and vomiting during the study. One patient (given ondansetron and metopimazine during the first course) reported mild nausea and a single retch two days before she received the second course, and one patient (given ondansetron during the first course) reported one to two retches but no nausea during the three days before the second course began. Since both patients expressed a preference for treatment with ondansetron and a placebo, the exclusion of these two patients from the analysis would only strengthen the superior results for ondansetron and metopimazine. A third patient, who reported no anticipatory nausea and vomiting after the first course (during treatment with ondansetron and metopimazine), reported one retch three days and one two days before the subsequent cycle of chemotherapy after completing this study.
Safety
Adverse events were common with both antiemetic treatments, but were generally mild (Table 4Table 4
Most Frequently Reported Adverse Events among 30 Patients Receiving Chemotherapy plus Ondansetron Alone or Ondansetron and Metopimazine.). The patients reported significantly more constipation during treatment with both ondansetron and metopimazine (P = 0.03). In addition to the adverse events reported in Table 4, patients receiving ondansetron and placebo reported shivering (two patients), flushing (one), abdominal pain (one), and a dry mouth (two). One patient had a brief episode of syncope, and one reported an itchy rash. Patients receiving ondansetron and metopimazine recorded shivering (two patients), flushing (one), a dry mouth (two), and palpitations (one). One patient had an itchy rash. Four patients classified an adverse event as severe (syncope, one; headache, one; dizziness, one; and flushing, one) in one of the two courses. The four patients were all receiving ondansetron and placebo at the time.Discussion
The serotonin antagonists have improved the treatment of acute chemotherapy-induced nausea and vomiting. Most trials have investigated patients undergoing chemotherapy for the first time, and impressively high rates of response have been obtained. Previous emesis with chemotherapy increases the likelihood of a poor response to antiemetics during subsequent cycles of the same type of chemotherapy29. This may explain why in this study only 47 percent of the patients receiving ondansetron alone had no emetic episodes on day 1, as compared with 60 to 66 percent in randomized trials of patients receiving their first course of moderately emetogenic chemotherapy7-9. The addition of metopimazine to the ondansetron regimen significantly reduced the occurrence of acute nausea and vomiting, with 63 percent of the patients reporting no acute emetic episodes.
In contrast to their success in the treatment of acute emesis, the serotonin antagonists seem less effective against delayed nausea and vomiting. Gandara et al.13 compared the antiemetic effect of ondansetron with that of placebo two to five days after cisplatin-based chemotherapy. Only on the fourth day after chemotherapy was given was ondansetron significantly superior in the control of emesis, whereas no significant difference was seen in the control of nausea. Most trials comparing ondansetron with metoclopramide demonstrated that ondansetron was significantly superior in the treatment of acute nausea and vomiting, but found no significant differences on days 2 through 55,8,14. In one study, metoclopramide afforded better protection against nausea on days 2 through 6,6 whereas in another,7 ondansetron significantly reduced emesis on days 2 and 3. In a randomized, double-blind trial, low-dose metoclopramide enhanced the effect of dexamethasone on delayed nausea and vomiting,30 suggesting that dopamine D2 antagonists may be of value as antiemetics two to five days after chemotherapy.
In this study, the combination of ondansetron and metopimazine significantly reduced the incidence of delayed nausea and vomiting. It is noteworthy that the addition of metopimazine led to the absence of severe delayed nausea and vomiting in all the patients (Table 2 and Table 3). Twenty-two patients had no emetic episodes and 8 had only one to two emetic episodes on days 2 through 5 during combination therapy; in contrast, 15 patients had emetic episodes during treatment with ondansetron alone, 7 of whom had three or more emetic episodes (P = 0.006). Severe delayed nausea was not seen with combination therapy, and only five patients reported moderate nausea, as compared with nine patients who reported moderate nausea and four patients severe nausea during treatment with ondansetron alone. Anticipatory nausea and vomiting were reported by only three patients in this study and seem to be minor problems in patients receiving moderately emetogenic chemotherapy.
This double-blind study confirms the results of an open, nonrandomized trial by Bregni et al.,31 of combination therapy with the dopamine antagonist haloperidol and the serotonin antagonist tropisetron. In a retrospective comparison, they found that this combination was superior to tropisetron alone. Other selective dopamine D2 antagonists, such as prochlorperazine and droperidol,32 have shown substantial antiemetic activity33,34 and might be useful in combination with serotonin antagonists. If used in such a combination, metoclopramide should probably be given in low conventional doses, since the antiemetic effect of high doses seems to be correlated with serotonin antagonism35.
Future trials should investigate other combinations of antiemetics with different mechanisms of action. For example, dexamethasone improves the antiemetic effect of ondansetron in patients receiving cisplatin-based chemotherapy10-12. A study of the combination of a serotonin antagonist, a dopamine D2 antagonist, and dexamethasone would be of interest.
Supported by the Foundation of E. Danielsen and Wife and by the Foundation of 1870.
Source Information
From the Department of Oncology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
Address reprint requests to Dr. Herrstedt at the Department of Oncology 54 B1, Herlev Hospital, Copenhagen DK-2730, Denmark.
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